Thesis, COLLÉGIALITÉ

Abstract

Despite their distinct embryonic origins and functions, pancreatic b cells and cortical neurons share molecular similarities. Mutations of some shared genes lead to monogenic forms of neonatal or young-onset diabetes associated with neurodevelopmental disorders (NDDs). These genes encode key proteins involved in the unfolded protein response (UPR) and the ER-to-Golgi trafficking. This project relies on the hypothesis that ER can instruct b cell and neuronal fate during development and life, whose disruption leads to diabetes associated with NDD. Upon the onset of corticogenesis apical progenitors undergo asymmetrical division to generate the first projection neurons by direct neurogenesis. As corticogenesis proceeds, the apical progenitors produce intermediate progenitors, which undergo symmetrical divisions and generate more projection neurons via indirect neurogenesis. Previous findings from the host lab showed that the progressive reduction of a physiological UPR in apical progenitors regulates the switch between direct and indirect neurogenesis. They also showed that pathological conditions associated with ER stress in apical progenitors can activate the PERK- branch of the UPR, leading to microcephaly as a result of increase direct neurogenesis and apoptosis of newborn projection neurons (Gladwyn-Ng et al., 2018; Laguesse et al., 2015). Here, I will focus on the physiological role of EIF2S3 a and TMEM167a genes and decipher how their mutations lead to microcephaly.